Blood stem cells give rise to all of our blood cells: the red blood cells that transport oxygen, the platelets that enable blood coagulation, and our immune cells that protect us from infections. Immune cells can, in turn, be divided into two groups; one that consists of cells with a very short life expectancy and a natural but rather unspecific ability to counteract infections (myeloid cells), and another that, in contrast, consists of very long-lived cells (lymphocytes) that specialize in combatting specific bacteria and viruses. “The ability of blood stem cells to form all types of blood cells is a fundamental property that is also utilized in connection with bone marrow transplants. An increased understanding of these processes is crucial as immune cells in patients who undergo bone marrow transplants are regenerated very slowly, which results in a long period of immune sensitivity”, says David Bryder who was in charge of the study. Despite the fact that all of our genes have been mapped, it is still largely unknown how the genes are controlled. What a cell can and cannot do is governed entirely by how the cell uses its genome. David Bryder and his colleagues have searched for genes expressed in immature blood cells but which disappear in connection with their further maturation. They then discovered the HLF gene, which caught their attention for two reasons: one, the gene controls what parts of our DNA are to be used, and two, the gene is directly involved in a rare but very aggressive type of blood cancer. “Our studies revealed that if the immature blood cells are unable to shut down the HLF gene at the correct stage of development, the lymphocytes – the long-lived immune cells – are unable to form. As a result, you will only have one type of immune defence.” A single cell must undergo a variety of changes to become cancerous. However, the earliest changes may involve the HLF gene, which give rise to a precursor to leukemia. Patients with leukemia in which the HLF gene is involved have a very poor prognosis, but it has been difficult to generate reliable models for studying the emergence, development and possible treatment of these leukemia more thoroughly. The researchers’ long-term goal is now to identify the mechanisms that can be used to break down these aggressive leukemia. “The knowledge and experimental model systems we developed concerning how HLF affects blood cell development enables us to map the order of gene mutations that lead to HLF-generated leukemia, which is an important next step towards our goal”, concludes David Bryder.
Lund Universityhttps://tinyurl.com/yd2xl6b2
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:51The HLF-gene controls the generation of our long-term immune system
Clearing a major hurdle in the field of microbiome research, Harvard Medical School scientists have designed and successfully used a method to tease out cause-and-effect relationships between gut bacteria and disease. The team says the approach could propel research beyond mere microbiome-disease associations and elucidate true cause-effect relationships. The experiments, conducted in mice, also identify a previously unknown gut microbe that tames intestinal inflammation and protects against severe colitis. The researchers say the finding makes a strong case for testing the newly identified gut bacterium as a probiotic therapy in people with inflammatory bowel disease, a constellation of conditions marked by chronic inflammation of the intestines and estimated to affect up to 1.3 million people in the United States, according to the Centers for Disease Control and Prevention. The approach uses a sort of “microbial triangulation.” It mimics the principles of classic maritime navigation or, in more modern terms, tracking the location of a mobile phone by verifying data from multiple sources—but instead of stars or cell phone towers, the researchers are homing in on intestinal bugs. Based on the method of elimination, the technique involves the gradual narrowing down of bacterial species to identify specific microbes that modulate the risk for specific diseases. In the current study, researchers adapted the principles to identify beneficial, protective bacteria. “Our approach can help scientists find the proverbial needles in a ‘haystack’ of thousands of microbes that are currently thought to modulate health,” said investigator Dennis Kasper, professor of microbiology and immunobiology at Harvard Medical School. “If the field is to move past associations—the Achilles’ heel in microbiome research—we need a system that reliably teases out causative relationships between gut bacteria and disease. We believe our method achieves that,” added Kasper, who is also the Harvard Medical School William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital. Over the last decade, study after study has identified thousands of commensal microbes—those residing innocently in our bodies—and catalogued observations of possible links between groups of microbes and the presence or absence of a panoply of diseases, including diabetes, multiple sclerosis and inflammatory bowel disease. Yet, scientists don’t know whether and how the presence of specific microbes—or fluctuations in their numbers—affects health. It remains unclear whether certain microbes are innocent bystanders, mere markers of disease, or whether they are active agents, causing harm or providing protection against certain ailments. The holy grail of this work would be not to merely define whether a microbe fuels or minimizes the risk for a given disease but to discover microbes and microbial molecules that can be used therapeutically. “The ultimate goal is to clarify the mechanisms of disease and then identify bacterial molecules that can be used to treat, reverse or prevent it,” said study lead author Neeraj Surana, Harvard Medical School instructor in pediatrics and an infectious disease specialist at Boston Children’s Hospital. For their study, Kasper and Surana compared the gut microbiomes of several groups of mice that harboured different populations of intestinal bacteria. The researchers started out with two groups of mice. One group had been bred with human gut microbiomes—housing intestinal bacteria normally found in human intestines. The other group had been bred to harbour normal mouse microbiomes. When researchers gave the animals a chemical compound that triggered intestinal inflammation, or colitis, mice that harboured human intestinal microbes were protected from the effects of the disease. Mice whose guts harboured typical mouse bacteria, however, developed severe symptoms. Next, the researchers housed all mice in the same living space. Sharing living space for as briefly as one day led to noticeable changes in how the animals responded to disease. Mice that had been originally protected from colitis started showing more serious signs of it, while colitis-prone mice grew increasingly resistant to the effects of the condition and developed milder symptoms—a proof-of-principle finding which shows that exchange of intestinal bacteria through shared living space can lead to changes in the animals’ ability to cope with the disease. The disease-modulating microbe would be lurking amid the hundreds of bacterial species present in all mice. But given that each mouse group harboured between 700 and 1,100 bacterial species in their guts, how could scientists identify the one that truly mattered in colitis? The team began by analysing the intestinal makeup of each one of the mouse groups, comparing their microbial profiles before and after they shared a living space. To “triangulate” the suspect’s identity, scientists looked for microbes that were either scarce or abundant, tracking with colitis severity. In other words, the numbers of the causative microbe would either go up or down with disease severity, the scientists reasoned. Only one such microbial group fit the profile—a bacterial family known as Lachnospiraceae, commonly found in human intestines as well as the guts of other mammals. To pinpoint the one organism within the Lachnospiraceae family that regulates response to colitis, the researchers isolated one bacterial species and gave it to colitis-prone mice. To compare its effects against other microbes, they also gave the animals organisms from different bacterial families. The only bacterium that protected colitis-prone animals from the ravages of the disease was a never-before-described microbe that the researchers had isolated from the guts of mice seeded with human feces, the animals that had harboured human microbiomes. The microbe was notably absent from mice with mouse microbiomes. Because of its immune-protective properties, Kasper and Surana christened the newly identified organism Clostridium immunis. The isolation of the disease-modifying microbe makes a powerful case for testing it as therapy in people with inflammatory bowel disease, the researchers said.
Harvard Medical Schoolhttps://tinyurl.com/yawe5qvh
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A report describes a new simple molecular test to detect chromosomal abnormalities — biomarkers known as telomere fusions–in pancreatic tumour specimens and pancreatic cyst fluids. This assay may help predict the presence of high-grade or invasive pancreatic cancers requiring surgical intervention. More sophisticated imaging of the pancreas has led to increased detection of presymptomatic lesions. The detection of telomere fusions has the potential to help physicians determine whether these lesions have a high likelihood of developing into pancreatic cancer requiring surgical resection or are more likely to be benign and can be followed by “watchful waiting.” “Clinicians rely on international consensus guidelines to help manage patients with pancreatic cancer precursor lesions such as intraductal papillary mucinous neoplasms (IPMNs). These guidelines are useful but pancreatic imaging does not provide sufficient information about the neoplastic nature of a pancreatic cyst. Better characterization of pancreatic cysts could allow more patients with worrisome cysts to continue with surveillance, avoiding the morbidity and risks related to pancreatic surgery,” explained Michael Goggins, MD, Sol Goldman Professor of Pancreatic Cancer Research, Departments of Pathology, Surgery, and Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine (Baltimore). Telomeres are regions of repetitive nucleotide sequences found at the ends of chromosomes that, under normal circumstances, keep the chromosome intact. When telomeres lose most or all of their telomere repeat sequences, the ends can fuse, leading to cell death or chromosomal instability. “This is a major mechanism that contributes to the progression of many precancerous neoplasms to invasive cancers,” said Dr. Goggins. “Telomere fusions can serve as a marker for predicting the presence of high-grade dysplasia and/or invasive cancer.” In this report, investigators describe a PCR-based assay to detect telomere fusions in samples of pancreatic tumour or cyst fluid. The assay incorporates two rounds of PCR with the second round using a telomere repeat probe to detect the fusions. The researchers analysed tissues from IPMN tumour samples taken from patients undergoing resection, surgical cyst fluid samples, and normal pancreas. IPMNs are the most common type of pancreatic neoplastic cysts. They are characterized by the papillary proliferation of mucin-producing epithelial cells and cystic dilatation of the main or branch pancreatic duct. This telomere fusion assay was able to identify telomere fusions in more than half of the pancreatic cell lines. Telomere fusions were often detected in tumours with high-grade dysplasia (containing more abnormal cells). Telomere fusions were not found in normal pancreas or samples with low-grade dysplasia. Similar findings were seen in analyses of cyst fluid, in which the presence of telomere fusions raised the likelihood of high-grade dysplasia or invasive cancer six fold. The telomere fusion events were found to be associated with high telomerase activity (an enzyme that lengthens telomeres) and shortened telomere length. “We have developed a simple molecular test to detect telomere fusions. This telomere fusion detection assay is a cheaper method for evaluating pancreatic cyst fluid than many next-generation sequencing approaches that are being evaluated for this purpose,” noted Dr. Goggins. “The authors succeed in showing the presence of shortened telomeres, sporadic telomeric fusions, and increased telomerase activity in a modest proportion of pancreatic lesions,” commented Loren Joseph, MD, of the Department of Pathology at Beth Israel Deaconess Medical Center, Harvard Medical School (Boston), in an accompanying editorial. He added that the techniques used to detect fusions from cyst DNA and to measure telomere length and telomerase activity are within the scope of many molecular diagnostic laboratories.
Science Articleshttps://tinyurl.com/y9mse347
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A gene which could play a role in causing the most severe cases of club foot has been identified by scientists at the University of Aberdeen. Clubfoot is a lower leg abnormality, where babies are born with the foot in a twisted position, facing inwards and upwards rather than flat to the floor. It is quite common, affecting about 1 baby in every 1,000 born in the UK. Of those, 1,000 about half have the condition in both feet. The causes of clubfoot are very poorly understood, though it sometimes runs in families and it is known that genes are involved. Experts believe the condition is a neuro-muscular problem – a result of muscle weakness in the legs during development. However it is difficult to pinpoint the causes because there are so many different things that can cause muscle weakness. The condition requires lengthy treatment involving manipulation, putting the feet in a cast (called the Ponseti method) an operation and then a requirement to wear specialised boots joined together by a metal bar at night until the age of four or five years old. In severe cases, which are often associated with failure of the nerves to calf muscles, even after this treatment the foot can bend back, meaning a more invasive surgery is required. The Aberdeen team believe they may have identified a gene in a mouse model which is linked to the more serious cases of clubfoot in humans. The gene (Limk1) is required for normal nerve growth and has shown to be part of a pathway of genes, one of which is already known to be linked to clubfoot in mice. Professor Martin Collinson, a geneticist from the University of Aberdeen, and leader of the study says: “This is, hopefully, another piece in the puzzle of what causes clubfoot in humans. Our hypothesis is that probably for most human clubfoot patients, it’s not just one gene that goes wrong, there are probably predisposed mutations in several genes in these pathways and they add up to eventually cause muscle weakness. “The next stage is to look at DNA samples taken from human clubfoot patients and screen them to see if there are mutations in these pathways. “Club foot is commonly treated successfully using the Ponseti method but it may be that the feet of children with these gene deformations will just revert back once treatment is finished. In theory if we could screen children for these genes before treatment starts, then they could avoid years of unnecessary interventions.” University of Aberdeenwww.abdn.ac.uk/news/11665/
Being on the cutting edge of science and technology excites Hollings Cancer Center (HCC) researcher Carsten Krieg, Ph.D. Each day, he walks into his lab that houses a mass cytometry machine aptly labelled Helios. Krieg explains how it can heat plasma up to 6,000 degrees Celsius, levels comparable to temperatures found on the sun. This allows the German native, who recently joined the faculty of the Medical University of South Carolina’s departments of immunology and dermatology, to accomplish an interesting feat. He creates a sort of ‘Instagram’ of a person’s immune system. For cancer patients on experimental immunotherapy treatments, the practical application is obvious and exciting, he said. “What I use here is a very new and nerdy technology, which is called mass cytometry, that allows you with a very high sensitivity to make pictures of your immune system. And this is possible because there’s artificial intelligence, machine learning combined with algorithms that can make a very complex system easy to visualize.” Basically, how it works is that researchers stain cells using rare metal-conjugated antibodies that target surface and intracellular proteins. “Normally in biological tissues, there are no rare metals, so this technique offers greater sensitivity in detecting targets.” Inside the Helios, the cells are ionized using an inductively-coupled plasma. The ions derived from each stained cell are maintained in discrete clouds that can be detected in a mass spectrometer. The technique can potentially detect up to 100 markers per cell, although, due to practical restrictions, about 40 are more realistic, he said. Then researchers use artificial intelligence and bioinformatics to create a two-dimensional mapping that can read the results, creating an Instagram of millions of blood cells. This is critical as Krieg and other cancer researchers hope to advance the field of immunotherapy. Though immunotherapy has shown great promise, the vast majority of patients either don’t respond, have adverse side effects or relapse. Krieg, who comes to HCC from the University Research Priority Program (URPP) in Zurich, Switzerland, wanted to know if the technology could be used to predict which patients might respond to certain treatments. While in Zurich, he and his colleagues decided to use the technique to study melanoma. The research identified biomarkers in the blood that can predict whether metastatic melanoma cancer patients will respond positively to immunotherapy. The goal was to see if a blood test for these biomarkers could identity those who are likelier to benefit, while allowing “non-responders” to begin other treatments without losing time, he said. “It’s a decision instrument for physicians and for the health care system.” It’s also a powerful research tool as it gets to the mechanisms behind what makes immunotherapy work. The recent study found an immune cell type known as classical monocytes in the peripheral blood may be a potential biomarker for patients who will respond to anti-PD-1 immune checkpoint therapy in metastatic melanoma. “Surprisingly, what we clearly found is that it’s the frequency of monocytes that is enhanced in responders over non-responders before immunotherapy.” Hollings Cancer Centeracademicdepartments.musc.edu/newscenter/2018/hcc-krieg-instagram/index.html
Researchers have identified specific genes that may trigger the development of sleep problems, and have also demonstrated a genetic link between insomnia and psychiatric disorders such as depression, or physical conditions such as type 2 diabetes. The study was led by Murray Stein of the University of California San Diego and the VA San Diego Healthcare System. Up to 20 percent of Americans and up to 50 percent of US military veterans are said to have trouble sleeping. The effects insomnia has on a person’s health can be debilitating and place a strain on the healthcare system. Chronic insomnia goes hand in hand with various long-term health issues such as heart disease and type 2 diabetes, as well as mental illness such as post-traumatic stress disorder (PTSD) and suicide. Twin studies have in the past shown that various sleep-related traits, including insomnia, are heritable. Based on these findings, researchers have started to look into the specific gene variants involved. Stein says such studies are important, given the vast range of reasons why people suffer from insomnia, and the different symptoms and varieties of sleeplessness that can be experienced. "A better understanding of the molecular bases for insomnia will be critical for the development of new treatments," he adds. In this study, Stein’s research team conducted genome-wide association studies (GWAS). DNA samples obtained from more than 33,000 soldiers participating in the Army Study To Assess Risk and Resilience in Service members (STARRS) were analysed. Data from soldiers of European, African and Latino descent were grouped separately as part of efforts to identify the influence of specific ancestral lineages. Stein and his colleagues also compared their results with those of two recent studies that used data from the UK Biobank. Overall, the study confirms that insomnia has a partially heritable basis. The researchers also found a strong genetic link between insomnia and type 2 diabetes. Among participants of European descent, there was additionally a genetic tie between sleeplessness and major depression. "The genetic correlation between insomnia disorder and other psychiatric disorders, such as major depression, and physical disorders such as type 2 diabetes suggests a shared genetic diathesis for these commonly co-occurring phenotypes," says Stein, who adds that the findings strengthen similar conclusions from prior twin and genome-wide association studies. Insomnia was linked to the occurrence of specific variants on chromosome 7. In people of European descent, there were also differences on chromosome 9. The variant on chromosome 7, for instance, is close to AUTS2, a gene that has been linked to alcohol consumption, as well as others that relate to brain development and sleep-related electric signalling. "Several of these variants rest comfortably among locations and pathways already known to be related to sleep and circadian rhythms," Stein elaborates. "Such insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease." EurekAlertwww.eurekalert.org/pub_releases/2018-03/s-csc030818.php
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A discovery sheds light on how cancerous cells differ from healthy ones, and could lead to the development of new strategies for therapeutic intervention for difficult-to-treat cancers in the future. An international team of investigators found a “stop sign”—a modified protein researchers named a PIP-stop—inside cells that are overused by cancerous cells that effectively prevents healthy ones from sorting material in the way they were designed to. “We have discovered that breast cancer, leukaemia, lymphoma and neuroblastoma cells have too many PIP-stops. This would upset protein function, and opens up a new avenue for developing drugs that block PIP-stop formation by kinase enzymes,” said Michael Overduin, a University of Alberta cancer researcher and professor of biochemistry, who led the research project. The team named the modification a PIP-stop because it stops proteins from interacting with lipid molecules called PIP. Before making their discovery, the researchers first solved the 3-D structure of a sorting nexin protein, which is key to sorting proteins to their proper locations within the cell. Powerful magnets in the U.K. and in the National High Field Nuclear Magnetic Resonance Centre (NANUC), Canada’s national magnet lab based in Edmonton, were then used to detect signals from within individual atoms within the protein structure. By focusing on the protein structure, the team was able to discover the PIP-stop and see how it blocked the protein’s function. The PIP-stop is a phosphate which is added to the protein surface that binds the PIP lipid, and normally controls how proteins attach to membranes. Samples from cancer patients have too many PIP-stops, which could lead to the unregulated growth seen in tumour cells. Similar PIP-stops were found to be overused in a large number of other proteins involved in other cancer types, where they could also influence tumour growth. “Our goal now is to design inhibitors for the overactive kinases that create PIP-stops, and to use this information to design drug molecules that block the progression of cancers, particularly those which lack effective treatments,” said Overduin. University of Alberta Faculty of Medicine & Dentistrywww.folio.ca/medical-researchers-find-protein-that-marks-difference-between-cancer-and-non-cancer-cells/
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Extremely low birth-weight babies are at risk for a chronic lung disease called bronchopulmonary dysplasia, or BPD. This condition can lead to death or long-term disease, but clinical measurements are unable to predict which of the tiny infants—who get care in hospital intensive-care units and often weigh just one and a half pounds—will develop BPD. University of Alabama at Birmingham researchers now report discovery of a strong predictive biomarker for BPD, and they show a role for the biomarker in the pathogenesis of this neonatal lung disease. These results open the path to possible future therapies to prevent or lessen BPD, which is marked by inflammation and impaired lung development. This biomarker could also help neonatologists plan optimal management and risk stratification of their tiny patients, and it could guide targeted enrolment of high-risk infants into randomized trials of potentially novel treatment strategies. The UAB work is an example of "bedside to bench" research. It began with prospective studies of extremely premature infants to identify potential biomarkers, and then proceeded to lab experiments using animal models and cells grown in culture to learn how the biomarker functions in disease progression. The study was led by Charitharth Vivek Lal, M.D., assistant professor in the UAB Pediatrics Division of Neonatology, and it builds upon Lal’s 2016 report that early microbial imbalance in the airways of extremely premature infants is predictive for development of BPD. The biomarker in the study is microRNA 876-3p. The hunt for the biomarker began with a prospective cohort study at the UAB Regional Neonatal Intensive Care Unit, looking at exosomes obtained from tracheal aspirates of infants with severe BPD, compared with full-term controls. Exosomes are small, membrane-bound blebs or vesicles that are actively secreted by a variety of cells. They are known to contain microRNAs and proteins, and the exosomes act in cell-to-cell signalling. MicroRNAs can regulate gene expression in cells. Lal and colleagues found that airway cells in infants with severe BPD had greater numbers of exosomes, but those exosomes were smaller sized. They also experimentally found that high oxygen exposure for newborn mice or human bronchial epithelial cells grown in culture also caused the release of more exosomes, and the exosomes were smaller in size that those secreted at normal oxygen level. Premature infants often receive extra oxygen to aid their underdeveloped lungs. The UAB researchers then did a prospective discovery cohort study at UAB—they collected tracheal aspirate samples from extremely premature infants within six hours of birth, purified exosomes from the samples and looked for microRNAs in the exosomes. Out of 810 microRNAs that were found, 40 showed differences between infants who later developed BPD and those who were BPD-resistant. Next, in cooperation with researchers at Thomas Jefferson University and Drexel University, a validation cohort was studied in Philadelphia. Thirty-two of the 40 microRNAs were confirmed; six had a higher statistical significance; and one biomarker, a low concentration of microRNA 876-3p, was found to have the highest sensitivity to predict severe BPD in extremely low birth-weight infants. Medical Xpressmedicalxpress.com/news/2018-03-exosomal-microrna-severe-lung-disease.html
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Research from the University of Liverpool identifies a genetic variant that could improve the safety and effectiveness of corticosteroids, drugs that are used to treat a range of common and rare conditions including asthma, and chronic obstructive pulmonary disease (COPD). Corticosteroids are very effective in the treatment of asthma and COPD, with more than 20 million prescriptions issued in the UK annually. Unfortunately, corticosteroids can also cause side effects, one of which is adrenal suppression, seen in up to 1/3 of people tested. People with this condition do not make enough cortisol. Cortisol helps the body respond to stress, recover from infections and regulate blood pressure and metabolism. Adrenal suppression can be very difficult to diagnose, as it can present with a spectrum of symptoms from non-specific symptoms such as tiredness, to serious illness and death. The majority of patients do not develop adrenal suppression, and the reasons why some do, and while other don’t, despite using similar doses of corticosteroids were not previously understood. In researchers from the University’s Institute of Translational Medicine, led by Professor Sir Munir Pirmohamed, conducted a genome-wide association study (GWAS) to pinpoint the genes responsible for increasing the risk of a person developing adrenal suppression. This method searches for single nucleotide polymorphisms (SNPs). Each person carries about three million SNPs, but if a particular SNP occurs more frequently in people with a particular condition than in people without the condition, it can pinpoint the underlying reason for the difference. The researchers identified two groups of children with asthma, and one group of adults with chronic obstructive pulmonary disease (COPD), all of whom used inhaled corticosteroid medications. Each patient’s adrenal function was tested. This is the largest published cohort of children ever tested for adrenal suppression (580 children in total). Individuals who had a particular variation in a specific gene (platelet derived growth factor D; PDGFD) had a markedly increased risk of adrenal suppression, both in the children with asthma and adults with COPD. This risk increased if the patient had two copies of the variation (one from their mother, one from their father). Children with two copies of the high risk variation in PDGFD were nearly six times more likely to develop adrenal suppression than children with no copies. University of Liverpoolnews.liverpool.ac.uk/2018/03/16/genetic-variant-discovery-to-help-asthma-sufferers/
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Atrial fibrillation (AF) is a heart condition that causes an irregular, and often rapid, heart rate. It increases the risk of developing strokes, heart failure, and even dementia. Although it can be associated with aging, high blood pressure, diabetes, heart valve problems, etc, about one-third of patients with AF have no symptoms until they suffer a stroke. Therefore, a means of identifying or predicting AF with the aim of starting preventative therapy is highly desirable. AF is associated with several factors that maintain its progression, including inflammation, electrical disturbances, and structural changes in the heart’s upper chambers (the atria). Moreover, several different short sequences of RNA known as microRNAs (miRNAs) have been linked with AF pathology. miRNAs control gene expression after the transcription stage, and have been suggested as possible markers for some cardiovascular diseases because of their stability in the bloodstream. However, it remains unknown whether the miRNAs shown to be related to AF are suitable as predictive biomarkers of disease. A team of researchers from Tokyo Medical and Dental University (TMDU) addressed this issue by comparing miRNA expression in AF patients and healthy controls, and between control mice and those with a similar abnormal heart rhythm to AF. They showed that four miRNAs not previously associated with AF were significantly upregulated in the serum of AF patients and diseased mice, indicating their potential use as AF biomarkers. The study results were recently published in Circulation Journal. Initially, human serum and mouse atrial tissue were screened for 733 and 672 miRNAs, respectively. These were eventually narrowed down to four by excluding non-detectable and non-specific miRNAs, and focusing on the quantification of their expression. “One of the miRNAs, miR-214-3p, is implicated in inflammation, so we wondered whether this might be the underlying mechanism of miRNA-induced AF pathology,” first author Yu Natsume says. “We compared miRNA expression with levels of a serum inflammatory factor but found no correlation suggestive of an association.” Statistical analysis of diagnostic ability showed that miR-214-3p and miR-342-5p had the highest accuracy as individual biomarkers at predicting AF, but that a combined analysis of all four miRNAs slightly improved this accuracy. “The same two miRNAs showed increased expression in a subset of patients with intermittent AF and another subset with chronic AF,” corresponding author Tetsuo Sasano says. “The increases were in comparison both with healthy controls of the same age and young healthy controls, suggesting these miRNAs may predict AF regardless of the age of the individual.” Tokyo Medical and Dental University (TMDU)www.tmd.ac.jp/english/press-release/20180313/index.html
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The HLF-gene controls the generation of our long-term immune system
, /in E-News /by 3wmediaBlood stem cells give rise to all of our blood cells: the red blood cells that transport oxygen, the platelets that enable blood coagulation, and our immune cells that protect us from infections. Immune cells can, in turn, be divided into two groups; one that consists of cells with a very short life expectancy and a natural but rather unspecific ability to counteract infections (myeloid cells), and another that, in contrast, consists of very long-lived cells (lymphocytes) that specialize in combatting specific bacteria and viruses.
“The ability of blood stem cells to form all types of blood cells is a fundamental property that is also utilized in connection with bone marrow transplants. An increased understanding of these processes is crucial as immune cells in patients who undergo bone marrow transplants are regenerated very slowly, which results in a long period of immune sensitivity”, says David Bryder who was in charge of the study.
Despite the fact that all of our genes have been mapped, it is still largely unknown how the genes are controlled. What a cell can and cannot do is governed entirely by how the cell uses its genome. David Bryder and his colleagues have searched for genes expressed in immature blood cells but which disappear in connection with their further maturation. They then discovered the HLF gene, which caught their attention for two reasons: one, the gene controls what parts of our DNA are to be used, and two, the gene is directly involved in a rare but very aggressive type of blood cancer.
“Our studies revealed that if the immature blood cells are unable to shut down the HLF gene at the correct stage of development, the lymphocytes – the long-lived immune cells – are unable to form. As a result, you will only have one type of immune defence.”
A single cell must undergo a variety of changes to become cancerous. However, the earliest changes may involve the HLF gene, which give rise to a precursor to leukemia. Patients with leukemia in which the HLF gene is involved have a very poor prognosis, but it has been difficult to generate reliable models for studying the emergence, development and possible treatment of these leukemia more thoroughly. The researchers’ long-term goal is now to identify the mechanisms that can be used to break down these aggressive leukemia.
“The knowledge and experimental model systems we developed concerning how HLF affects blood cell development enables us to map the order of gene mutations that lead to HLF-generated leukemia, which is an important next step towards our goal”, concludes David Bryder.
Lund Universityhttps://tinyurl.com/yd2xl6b2
Needle in a haystack
, /in E-News /by 3wmediaClearing a major hurdle in the field of microbiome research, Harvard Medical School scientists have designed and successfully used a method to tease out cause-and-effect relationships between gut bacteria and disease.
The team says the approach could propel research beyond mere microbiome-disease associations and elucidate true cause-effect relationships.
The experiments, conducted in mice, also identify a previously unknown gut microbe that tames intestinal inflammation and protects against severe colitis. The researchers say the finding makes a strong case for testing the newly identified gut bacterium as a probiotic therapy in people with inflammatory bowel disease, a constellation of conditions marked by chronic inflammation of the intestines and estimated to affect up to 1.3 million people in the United States, according to the Centers for Disease Control and Prevention.
The approach uses a sort of “microbial triangulation.” It mimics the principles of classic maritime navigation or, in more modern terms, tracking the location of a mobile phone by verifying data from multiple sources—but instead of stars or cell phone towers, the researchers are homing in on intestinal bugs. Based on the method of elimination, the technique involves the gradual narrowing down of bacterial species to identify specific microbes that modulate the risk for specific diseases. In the current study, researchers adapted the principles to identify beneficial, protective bacteria.
“Our approach can help scientists find the proverbial needles in a ‘haystack’ of thousands of microbes that are currently thought to modulate health,” said investigator Dennis Kasper, professor of microbiology and immunobiology at Harvard Medical School. “If the field is to move past associations—the Achilles’ heel in microbiome research—we need a system that reliably teases out causative relationships between gut bacteria and disease. We believe our method achieves that,” added Kasper, who is also the Harvard Medical School William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital.
Over the last decade, study after study has identified thousands of commensal microbes—those residing innocently in our bodies—and catalogued observations of possible links between groups of microbes and the presence or absence of a panoply of diseases, including diabetes, multiple sclerosis and inflammatory bowel disease. Yet, scientists don’t know whether and how the presence of specific microbes—or fluctuations in their numbers—affects health. It remains unclear whether certain microbes are innocent bystanders, mere markers of disease, or whether they are active agents, causing harm or providing protection against certain ailments.
The holy grail of this work would be not to merely define whether a microbe fuels or minimizes the risk for a given disease but to discover microbes and microbial molecules that can be used therapeutically.
“The ultimate goal is to clarify the mechanisms of disease and then identify bacterial molecules that can be used to treat, reverse or prevent it,” said study lead author Neeraj Surana, Harvard Medical School instructor in pediatrics and an infectious disease specialist at Boston Children’s Hospital.
For their study, Kasper and Surana compared the gut microbiomes of several groups of mice that harboured different populations of intestinal bacteria.
The researchers started out with two groups of mice. One group had been bred with human gut microbiomes—housing intestinal bacteria normally found in human intestines. The other group had been bred to harbour normal mouse microbiomes. When researchers gave the animals a chemical compound that triggered intestinal inflammation, or colitis, mice that harboured human intestinal microbes were protected from the effects of the disease. Mice whose guts harboured typical mouse bacteria, however, developed severe symptoms.
Next, the researchers housed all mice in the same living space. Sharing living space for as briefly as one day led to noticeable changes in how the animals responded to disease. Mice that had been originally protected from colitis started showing more serious signs of it, while colitis-prone mice grew increasingly resistant to the effects of the condition and developed milder symptoms—a proof-of-principle finding which shows that exchange of intestinal bacteria through shared living space can lead to changes in the animals’ ability to cope with the disease.
The disease-modulating microbe would be lurking amid the hundreds of bacterial species present in all mice. But given that each mouse group harboured between 700 and 1,100 bacterial species in their guts, how could scientists identify the one that truly mattered in colitis? The team began by analysing the intestinal makeup of each one of the mouse groups, comparing their microbial profiles before and after they shared a living space. To “triangulate” the suspect’s identity, scientists looked for microbes that were either scarce or abundant, tracking with colitis severity. In other words, the numbers of the causative microbe would either go up or down with disease severity, the scientists reasoned. Only one such microbial group fit the profile—a bacterial family known as Lachnospiraceae, commonly found in human intestines as well as the guts of other mammals.
To pinpoint the one organism within the Lachnospiraceae family that regulates response to colitis, the researchers isolated one bacterial species and gave it to colitis-prone mice. To compare its effects against other microbes, they also gave the animals organisms from different bacterial families. The only bacterium that protected colitis-prone animals from the ravages of the disease was a never-before-described microbe that the researchers had isolated from the guts of mice seeded with human feces, the animals that had harboured human microbiomes. The microbe was notably absent from mice with mouse microbiomes. Because of its immune-protective properties, Kasper and Surana christened the newly identified organism Clostridium immunis.
The isolation of the disease-modifying microbe makes a powerful case for testing it as therapy in people with inflammatory bowel disease, the researchers said.
Harvard Medical Schoolhttps://tinyurl.com/yawe5qvh
New assay may help predict which pancreatic lesions may become cancerous
, /in E-News /by 3wmediaA report describes a new simple molecular test to detect chromosomal abnormalities — biomarkers known as telomere fusions–in pancreatic tumour specimens and pancreatic cyst fluids. This assay may help predict the presence of high-grade or invasive pancreatic cancers requiring surgical intervention.
More sophisticated imaging of the pancreas has led to increased detection of presymptomatic lesions. The detection of telomere fusions has the potential to help physicians determine whether these lesions have a high likelihood of developing into pancreatic cancer requiring surgical resection or are more likely to be benign and can be followed by “watchful waiting.”
“Clinicians rely on international consensus guidelines to help manage patients with pancreatic cancer precursor lesions such as intraductal papillary mucinous neoplasms (IPMNs). These guidelines are useful but pancreatic imaging does not provide sufficient information about the neoplastic nature of a pancreatic cyst. Better characterization of pancreatic cysts could allow more patients with worrisome cysts to continue with surveillance, avoiding the morbidity and risks related to pancreatic surgery,” explained Michael Goggins, MD, Sol Goldman Professor of Pancreatic Cancer Research, Departments of Pathology, Surgery, and Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine (Baltimore).
Telomeres are regions of repetitive nucleotide sequences found at the ends of chromosomes that, under normal circumstances, keep the chromosome intact. When telomeres lose most or all of their telomere repeat sequences, the ends can fuse, leading to cell death or chromosomal instability. “This is a major mechanism that contributes to the progression of many precancerous neoplasms to invasive cancers,” said Dr. Goggins. “Telomere fusions can serve as a marker for predicting the presence of high-grade dysplasia and/or invasive cancer.”
In this report, investigators describe a PCR-based assay to detect telomere fusions in samples of pancreatic tumour or cyst fluid. The assay incorporates two rounds of PCR with the second round using a telomere repeat probe to detect the fusions.
The researchers analysed tissues from IPMN tumour samples taken from patients undergoing resection, surgical cyst fluid samples, and normal pancreas. IPMNs are the most common type of pancreatic neoplastic cysts. They are characterized by the papillary proliferation of mucin-producing epithelial cells and cystic dilatation of the main or branch pancreatic duct.
This telomere fusion assay was able to identify telomere fusions in more than half of the pancreatic cell lines. Telomere fusions were often detected in tumours with high-grade dysplasia (containing more abnormal cells). Telomere fusions were not found in normal pancreas or samples with low-grade dysplasia.
Similar findings were seen in analyses of cyst fluid, in which the presence of telomere fusions raised the likelihood of high-grade dysplasia or invasive cancer six fold. The telomere fusion events were found to be associated with high telomerase activity (an enzyme that lengthens telomeres) and shortened telomere length.
“We have developed a simple molecular test to detect telomere fusions. This telomere fusion detection assay is a cheaper method for evaluating pancreatic cyst fluid than many next-generation sequencing approaches that are being evaluated for this purpose,” noted Dr. Goggins.
“The authors succeed in showing the presence of shortened telomeres, sporadic telomeric fusions, and increased telomerase activity in a modest proportion of pancreatic lesions,” commented Loren Joseph, MD, of the Department of Pathology at Beth Israel Deaconess Medical Center, Harvard Medical School (Boston), in an accompanying editorial. He added that the techniques used to detect fusions from cyst DNA and to measure telomere length and telomerase activity are within the scope of many molecular diagnostic laboratories.
Science Articleshttps://tinyurl.com/y9mse347
‘Clubfoot’ gene identified
, /in E-News /by 3wmediaA gene which could play a role in causing the most severe cases of club foot has been identified by scientists at the University of Aberdeen.
Clubfoot is a lower leg abnormality, where babies are born with the foot in a twisted position, facing inwards and upwards rather than flat to the floor. It is quite common, affecting about 1 baby in every 1,000 born in the UK. Of those, 1,000 about half have the condition in both feet.
The causes of clubfoot are very poorly understood, though it sometimes runs in families and it is known that genes are involved.
Experts believe the condition is a neuro-muscular problem – a result of muscle weakness in the legs during development. However it is difficult to pinpoint the causes because there are so many different things that can cause muscle weakness.
The condition requires lengthy treatment involving manipulation, putting the feet in a cast (called the Ponseti method) an operation and then a requirement to wear specialised boots joined together by a metal bar at night until the age of four or five years old.
In severe cases, which are often associated with failure of the nerves to calf muscles, even after this treatment the foot can bend back, meaning a more invasive surgery is required.
The Aberdeen team believe they may have identified a gene in a mouse model which is linked to the more serious cases of clubfoot in humans.
The gene (Limk1) is required for normal nerve growth and has shown to be part of a pathway of genes, one of which is already known to be linked to clubfoot in mice.
Professor Martin Collinson, a geneticist from the University of Aberdeen, and leader of the study says: “This is, hopefully, another piece in the puzzle of what causes clubfoot in humans. Our hypothesis is that probably for most human clubfoot patients, it’s not just one gene that goes wrong, there are probably predisposed mutations in several genes in these pathways and they add up to eventually cause muscle weakness.
“The next stage is to look at DNA samples taken from human clubfoot patients and screen them to see if there are mutations in these pathways.
“Club foot is commonly treated successfully using the Ponseti method but it may be that the feet of children with these gene deformations will just revert back once treatment is finished. In theory if we could screen children for these genes before treatment starts, then they could avoid years of unnecessary interventions.”
University of Aberdeenwww.abdn.ac.uk/news/11665/
Researcher creates ‘Instagram’ of immune system, blending science, technology
, /in E-News /by 3wmediaBeing on the cutting edge of science and technology excites Hollings Cancer Center (HCC) researcher Carsten Krieg, Ph.D. Each day, he walks into his lab that houses a mass cytometry machine aptly labelled Helios. Krieg explains how it can heat plasma up to 6,000 degrees Celsius, levels comparable to temperatures found on the sun.
This allows the German native, who recently joined the faculty of the Medical University of South Carolina’s departments of immunology and dermatology, to accomplish an interesting feat. He creates a sort of ‘Instagram’ of a person’s immune system. For cancer patients on experimental immunotherapy treatments, the practical application is obvious and exciting, he said.
“What I use here is a very new and nerdy technology, which is called mass cytometry, that allows you with a very high sensitivity to make pictures of your immune system. And this is possible because there’s artificial intelligence, machine learning combined with algorithms that can make a very complex system easy to visualize.”
Basically, how it works is that researchers stain cells using rare metal-conjugated antibodies that target surface and intracellular proteins. “Normally in biological tissues, there are no rare metals, so this technique offers greater sensitivity in detecting targets.”
Inside the Helios, the cells are ionized using an inductively-coupled plasma. The ions derived from each stained cell are maintained in discrete clouds that can be detected in a mass spectrometer. The technique can potentially detect up to 100 markers per cell, although, due to practical restrictions, about 40 are more realistic, he said. Then researchers use artificial intelligence and bioinformatics to create a two-dimensional mapping that can read the results, creating an Instagram of millions of blood cells.
This is critical as Krieg and other cancer researchers hope to advance the field of immunotherapy. Though immunotherapy has shown great promise, the vast majority of patients either don’t respond, have adverse side effects or relapse. Krieg, who comes to HCC from the University Research Priority Program (URPP) in Zurich, Switzerland, wanted to know if the technology could be used to predict which patients might respond to certain treatments.
While in Zurich, he and his colleagues decided to use the technique to study melanoma. The research identified biomarkers in the blood that can predict whether metastatic melanoma cancer patients will respond positively to immunotherapy. The goal was to see if a blood test for these biomarkers could identity those who are likelier to benefit, while allowing “non-responders” to begin other treatments without losing time, he said. “It’s a decision instrument for physicians and for the health care system.”
It’s also a powerful research tool as it gets to the mechanisms behind what makes immunotherapy work. The recent study found an immune cell type known as classical monocytes in the peripheral blood may be a potential biomarker for patients who will respond to anti-PD-1 immune checkpoint therapy in metastatic melanoma. “Surprisingly, what we clearly found is that it’s the frequency of monocytes that is enhanced in responders over non-responders before immunotherapy.”
Hollings Cancer Centeracademicdepartments.musc.edu/newscenter/2018/hcc-krieg-instagram/index.html
Can’t sleep? Could be down to genetics
, /in E-News /by 3wmediaResearchers have identified specific genes that may trigger the development of sleep problems, and have also demonstrated a genetic link between insomnia and psychiatric disorders such as depression, or physical conditions such as type 2 diabetes. The study was led by Murray Stein of the University of California San Diego and the VA San Diego Healthcare System.
Up to 20 percent of Americans and up to 50 percent of US military veterans are said to have trouble sleeping. The effects insomnia has on a person’s health can be debilitating and place a strain on the healthcare system. Chronic insomnia goes hand in hand with various long-term health issues such as heart disease and type 2 diabetes, as well as mental illness such as post-traumatic stress disorder (PTSD) and suicide.
Twin studies have in the past shown that various sleep-related traits, including insomnia, are heritable. Based on these findings, researchers have started to look into the specific gene variants involved. Stein says such studies are important, given the vast range of reasons why people suffer from insomnia, and the different symptoms and varieties of sleeplessness that can be experienced.
"A better understanding of the molecular bases for insomnia will be critical for the development of new treatments," he adds.
In this study, Stein’s research team conducted genome-wide association studies (GWAS). DNA samples obtained from more than 33,000 soldiers participating in the Army Study To Assess Risk and Resilience in Service members (STARRS) were analysed. Data from soldiers of European, African and Latino descent were grouped separately as part of efforts to identify the influence of specific ancestral lineages. Stein and his colleagues also compared their results with those of two recent studies that used data from the UK Biobank.
Overall, the study confirms that insomnia has a partially heritable basis. The researchers also found a strong genetic link between insomnia and type 2 diabetes. Among participants of European descent, there was additionally a genetic tie between sleeplessness and major depression.
"The genetic correlation between insomnia disorder and other psychiatric disorders, such as major depression, and physical disorders such as type 2 diabetes suggests a shared genetic diathesis for these commonly co-occurring phenotypes," says Stein, who adds that the findings strengthen similar conclusions from prior twin and genome-wide association studies.
Insomnia was linked to the occurrence of specific variants on chromosome 7. In people of European descent, there were also differences on chromosome 9. The variant on chromosome 7, for instance, is close to AUTS2, a gene that has been linked to alcohol consumption, as well as others that relate to brain development and sleep-related electric signalling.
"Several of these variants rest comfortably among locations and pathways already known to be related to sleep and circadian rhythms," Stein elaborates. "Such insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease."
EurekAlertwww.eurekalert.org/pub_releases/2018-03/s-csc030818.php
Medical researchers find protein that marks difference between cancer and non-cancer cells
, /in E-News /by 3wmediaA discovery sheds light on how cancerous cells differ from healthy ones, and could lead to the development of new strategies for therapeutic intervention for difficult-to-treat cancers in the future.
An international team of investigators found a “stop sign”—a modified protein researchers named a PIP-stop—inside cells that are overused by cancerous cells that effectively prevents healthy ones from sorting material in the way they were designed to.
“We have discovered that breast cancer, leukaemia, lymphoma and neuroblastoma cells have too many PIP-stops. This would upset protein function, and opens up a new avenue for developing drugs that block PIP-stop formation by kinase enzymes,” said Michael Overduin, a University of Alberta cancer researcher and professor of biochemistry, who led the research project.
The team named the modification a PIP-stop because it stops proteins from interacting with lipid molecules called PIP.
Before making their discovery, the researchers first solved the 3-D structure of a sorting nexin protein, which is key to sorting proteins to their proper locations within the cell. Powerful magnets in the U.K. and in the National High Field Nuclear Magnetic Resonance Centre (NANUC), Canada’s national magnet lab based in Edmonton, were then used to detect signals from within individual atoms within the protein structure.
By focusing on the protein structure, the team was able to discover the PIP-stop and see how it blocked the protein’s function. The PIP-stop is a phosphate which is added to the protein surface that binds the PIP lipid, and normally controls how proteins attach to membranes.
Samples from cancer patients have too many PIP-stops, which could lead to the unregulated growth seen in tumour cells. Similar PIP-stops were found to be overused in a large number of other proteins involved in other cancer types, where they could also influence tumour growth.
“Our goal now is to design inhibitors for the overactive kinases that create PIP-stops, and to use this information to design drug molecules that block the progression of cancers, particularly those which lack effective treatments,” said Overduin.
University of Alberta Faculty of Medicine & Dentistrywww.folio.ca/medical-researchers-find-protein-that-marks-difference-between-cancer-and-non-cancer-cells/
Exosomal microRNA predicts and protects against severe lung disease in extremely premature infants
, /in E-News /by 3wmediaUniversity of Alabama at Birmingham researchers now report discovery of a strong predictive biomarker for BPD, and they show a role for the biomarker in the pathogenesis of this neonatal lung disease. These results open the path to possible future therapies to prevent or lessen BPD, which is marked by inflammation and impaired lung development.
This biomarker could also help neonatologists plan optimal management and risk stratification of their tiny patients, and it could guide targeted enrolment of high-risk infants into randomized trials of potentially novel treatment strategies.
The UAB work is an example of "bedside to bench" research. It began with prospective studies of extremely premature infants to identify potential biomarkers, and then proceeded to lab experiments using animal models and cells grown in culture to learn how the biomarker functions in disease progression.
The study was led by Charitharth Vivek Lal, M.D., assistant professor in the UAB Pediatrics Division of Neonatology, and it builds upon Lal’s 2016 report that early microbial imbalance in the airways of extremely premature infants is predictive for development of BPD.
The biomarker in the study is microRNA 876-3p.
The hunt for the biomarker began with a prospective cohort study at the UAB Regional Neonatal Intensive Care Unit, looking at exosomes obtained from tracheal aspirates of infants with severe BPD, compared with full-term controls. Exosomes are small, membrane-bound blebs or vesicles that are actively secreted by a variety of cells. They are known to contain microRNAs and proteins, and the exosomes act in cell-to-cell signalling. MicroRNAs can regulate gene expression in cells.
Lal and colleagues found that airway cells in infants with severe BPD had greater numbers of exosomes, but those exosomes were smaller sized. They also experimentally found that high oxygen exposure for newborn mice or human bronchial epithelial cells grown in culture also caused the release of more exosomes, and the exosomes were smaller in size that those secreted at normal oxygen level. Premature infants often receive extra oxygen to aid their underdeveloped lungs.
The UAB researchers then did a prospective discovery cohort study at UAB—they collected tracheal aspirate samples from extremely premature infants within six hours of birth, purified exosomes from the samples and looked for microRNAs in the exosomes. Out of 810 microRNAs that were found, 40 showed differences between infants who later developed BPD and those who were BPD-resistant.
Next, in cooperation with researchers at Thomas Jefferson University and Drexel University, a validation cohort was studied in Philadelphia. Thirty-two of the 40 microRNAs were confirmed; six had a higher statistical significance; and one biomarker, a low concentration of microRNA 876-3p, was found to have the highest sensitivity to predict severe BPD in extremely low birth-weight infants.
Medical Xpressmedicalxpress.com/news/2018-03-exosomal-microrna-severe-lung-disease.html
Genetic variant discovery to help asthma sufferers
, /in E-News /by 3wmediaResearch from the University of Liverpool identifies a genetic variant that could improve the safety and effectiveness of corticosteroids, drugs that are used to treat a range of common and rare conditions including asthma, and chronic obstructive pulmonary disease (COPD).
Corticosteroids are very effective in the treatment of asthma and COPD, with more than 20 million prescriptions issued in the UK annually. Unfortunately, corticosteroids can also cause side effects, one of which is adrenal suppression, seen in up to 1/3 of people tested. People with this condition do not make enough cortisol. Cortisol helps the body respond to stress, recover from infections and regulate blood pressure and metabolism.
Adrenal suppression can be very difficult to diagnose, as it can present with a spectrum of symptoms from non-specific symptoms such as tiredness, to serious illness and death. The majority of patients do not develop adrenal suppression, and the reasons why some do, and while other don’t, despite using similar doses of corticosteroids were not previously understood.
In researchers from the University’s Institute of Translational Medicine, led by Professor Sir Munir Pirmohamed, conducted a genome-wide association study (GWAS) to pinpoint the genes responsible for increasing the risk of a person developing adrenal suppression. This method searches for single nucleotide polymorphisms (SNPs). Each person carries about three million SNPs, but if a particular SNP occurs more frequently in people with a particular condition than in people without the condition, it can pinpoint the underlying reason for the difference.
The researchers identified two groups of children with asthma, and one group of adults with chronic obstructive pulmonary disease (COPD), all of whom used inhaled corticosteroid medications. Each patient’s adrenal function was tested. This is the largest published cohort of children ever tested for adrenal suppression (580 children in total).
Individuals who had a particular variation in a specific gene (platelet derived growth factor D; PDGFD) had a markedly increased risk of adrenal suppression, both in the children with asthma and adults with COPD. This risk increased if the patient had two copies of the variation (one from their mother, one from their father). Children with two copies of the high risk variation in PDGFD were nearly six times more likely to develop adrenal suppression than children with no copies.
University of Liverpoolnews.liverpool.ac.uk/2018/03/16/genetic-variant-discovery-to-help-asthma-sufferers/
Potential RNA markers of abnormal heart rhythms identified
, /in E-News /by 3wmediaAtrial fibrillation (AF) is a heart condition that causes an irregular, and often rapid, heart rate. It increases the risk of developing strokes, heart failure, and even dementia. Although it can be associated with aging, high blood pressure, diabetes, heart valve problems, etc, about one-third of patients with AF have no symptoms until they suffer a stroke. Therefore, a means of identifying or predicting AF with the aim of starting preventative therapy is highly desirable.
AF is associated with several factors that maintain its progression, including inflammation, electrical disturbances, and structural changes in the heart’s upper chambers (the atria). Moreover, several different short sequences of RNA known as microRNAs (miRNAs) have been linked with AF pathology. miRNAs control gene expression after the transcription stage, and have been suggested as possible markers for some cardiovascular diseases because of their stability in the bloodstream. However, it remains unknown whether the miRNAs shown to be related to AF are suitable as predictive biomarkers of disease.
A team of researchers from Tokyo Medical and Dental University (TMDU) addressed this issue by comparing miRNA expression in AF patients and healthy controls, and between control mice and those with a similar abnormal heart rhythm to AF. They showed that four miRNAs not previously associated with AF were significantly upregulated in the serum of AF patients and diseased mice, indicating their potential use as AF biomarkers. The study results were recently published in Circulation Journal.
Initially, human serum and mouse atrial tissue were screened for 733 and 672 miRNAs, respectively. These were eventually narrowed down to four by excluding non-detectable and non-specific miRNAs, and focusing on the quantification of their expression.
“One of the miRNAs, miR-214-3p, is implicated in inflammation, so we wondered whether this might be the underlying mechanism of miRNA-induced AF pathology,” first author Yu Natsume says. “We compared miRNA expression with levels of a serum inflammatory factor but found no correlation suggestive of an association.”
Statistical analysis of diagnostic ability showed that miR-214-3p and miR-342-5p had the highest accuracy as individual biomarkers at predicting AF, but that a combined analysis of all four miRNAs slightly improved this accuracy.
“The same two miRNAs showed increased expression in a subset of patients with intermittent AF and another subset with chronic AF,” corresponding author Tetsuo Sasano says. “The increases were in comparison both with healthy controls of the same age and young healthy controls, suggesting these miRNAs may predict AF regardless of the age of the individual.”
Tokyo Medical and Dental University (TMDU)www.tmd.ac.jp/english/press-release/20180313/index.html